A new class of arylpiperazine derivatives: the library synthesis on SynPhase lanterns and biological evaluation on serotonin 5-HT(1A) and 5-HT(2A) receptors

Journal of Combinatorial Chemistry
Paweł ZajdelJean Martinez

Abstract

An efficient solid-supported method for the synthesis of a new class of arylpiperazine derivatives containing amino acid residues has been developed. A 72-membered library was synthesized on SynPhase Lanterns functionalized by a BAL linker. A one-pot cleavage/cyclization step of aspartic and glutamic acid derivatives yielded succinimide- and pyroglutamyl-containing ligands (chemsets 9 and 10). The library representatives under study showed different levels of affinity for 5-HT(1A) and 5-HT(2A) receptors (estimated K(i) = 24-4000 and 1-2130 nM, respectively). Several dual 5-HT(1A)/5-HT(2A) ligands were found, of which two (9(3,3) and 9(3,5)) displayed high 5-HT(2A) affinity comparable to that of the reference drug ritanserin. A set of individual fragment contributions for the prediction of 5-HT(1A) and 5-HT(2A) affinity of all the library members were defined on the basis of the Free-Wilson analysis of 26 compounds. An alkylarylpiperazine fragment had essentially the same impact on the affinity for both receptors, whereas different terminal amide fragments were preferred by 5-HT(1A) (chemset 17, R(2) = adamantyl) and 5-HT(2A) (chemset 9, R(2) = norborn-2-ylmethyl) binding sites.

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Citations

Feb 26, 2013·Chemical Reviews·Lukas WankaPeter R Schreiner
Jul 27, 2010·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·William L ScottMartin J O'Donnell
Jul 25, 2012·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·Paul R Albert
May 15, 2010·Chemistry : a European Journal·Paweł ZajdelGilles Subra
Jul 23, 2019·Progress in Neuro-psychopharmacology & Biological Psychiatry·Hatylas AzevedoCristiano Ruch Werneck Guimarães
Mar 18, 2009·Chemical Reviews·Ulrik BoasKnud J Jensen
Aug 19, 2010·Journal of Combinatorial Chemistry·Pawel ZajdelGilles Subra
Nov 15, 2005·Journal of Combinatorial Chemistry·Roland E Dolle

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